WO2017031994A1 - 曲沙他滨的合成及其晶型 - Google Patents

曲沙他滨的合成及其晶型 Download PDF

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WO2017031994A1
WO2017031994A1 PCT/CN2016/079606 CN2016079606W WO2017031994A1 WO 2017031994 A1 WO2017031994 A1 WO 2017031994A1 CN 2016079606 W CN2016079606 W CN 2016079606W WO 2017031994 A1 WO2017031994 A1 WO 2017031994A1
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compound
formula
formula iii
methanol
crystal
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PCT/CN2016/079606
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French (fr)
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周•詹姆斯
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北京慧宝源生物技术有限公司
广西慧宝源医药科技有限公司
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Priority to US15/755,130 priority Critical patent/US11731959B2/en
Publication of WO2017031994A1 publication Critical patent/WO2017031994A1/zh

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs

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  • the present invention belongs to the field of medicinal chemistry, and in particular, the present invention relates to a method for synthesizing trathacitabine, a crystal form thereof and the like.
  • Troxacitabine (4-amino -1 - [(2S, 4S) -2- ( hydroxymethyl) -1,3-dioxolan-4-yl] pyrimidin-2-one, Troxacitabine, Troxatyl TM ) is an anti-tumor cytidine analog developed by Yale University.
  • troxacitab was administered alone or in combination with other chemotherapeutic agents in various dose regimens, treating more than 825 patients with multiple solid tumors or blood. A patient with a malignant tumor.
  • troxacitab has the property of inhibiting the growth of hepatitis B virus and anti-hepatoma cells.
  • Chinese Patent Application No. 201310275643.2 discloses a method for synthesizing troxacitabine, which uses L-menthol ester of dihydroxyacetic acid as a raw material to undergo condensation reaction with hydroxyacetaldehyde, and then halogenated to obtain a halogenated product.
  • the halogenated substance is coupled with cytosine to obtain a coupling, and the coupling is further reduced to obtain troxacitabine.
  • the method requires four steps of condensation, halogenation, coupling, and reduction, which are required to be carried out in different reaction systems. The steps are long and cumbersome, especially in intermediate products, requiring multiple separations and replacement reactions.
  • the container is not suitable for magnification, so it is not suitable for industrial production.
  • the present invention provides a method for synthesizing trozaplatin, a crystal of trazacitabine, a method of crystal crystallization, and application of a crystal.
  • the present invention provides a method for synthesizing a compound of formula III, the synthesis of which is shown below:
  • the present invention provides a crystal of the compound of Formula III (Form A) having an X-ray powder diffraction pattern substantially as shown in Figure 1 or 7.
  • the present invention provides a method of crystallizing Form A comprising: heating a compound of Formula III to 80 ° C in an oven, maintaining the temperature for 10 minutes, and naturally cooling to room temperature.
  • the present invention provides a crystal (Form C) of a monohydrate of a compound of Formula III having an X-ray powder diffraction pattern substantially as shown in Figure 4.
  • the present invention provides a crystallization method of Form C, which comprises: dissolving a compound of Formula III in water, volatilizing in a fume hood for 3 days, then moving into a vacuum drying oven, and vacuuming the open vacuum 1 day.
  • the present invention provides a crystal of the compound of Formula III (Form E) having an X-ray powder diffraction pattern substantially as shown in FIG.
  • the present invention provides a crystallization method of Form E, which comprises: adding a compound of Formula III to methanol and acetone, wherein the volume ratio of methanol:acetone is 1:9, and the suspension is stirred for 3 days at 10,000 rpm. The mixture was centrifuged for 3 minutes, and the precipitate was dried under vacuum for 1 hour.
  • the invention provides a solid pharmaceutical formulation comprising Form A, Form C and/or Form E, and a pharmaceutically acceptable excipient.
  • the invention provides the use of Form A, Form C and/or Form E for the preparation of a medicament for anti-tumor and/or anti-viral.
  • the synthesis method of the first aspect of the invention is a novel synthesis method of trastazin.
  • the method comprises a two-step chemical reaction and a corresponding purification method, which is suitable for industrial production.
  • a preferred synthesis method of the first aspect of the invention comprises:
  • the compound of the formula I dichloromethane: trimethyliodosilane: hexamethyldisilazane: N 4 -acetyl
  • the weight ratio of pyrimidine is 1:18.0:1.5:3.64:1.15.
  • the weight ratio of the compound of the formula II: methanol is 1:0.045.
  • a silica gel column is used, and the eluent is dichloromethane and methanol. Further preferably, the volume ratio of dichloromethane:methanol is 4:1.
  • the synthesis method of the first aspect of the invention comprises a step of crystallization, that is, a step of further crystallization after completion of the purification step of the step (2).
  • the step of crystallizing is selected from one of the following (a), (b) and (c):
  • the crystal of the second aspect of the invention is also referred to herein as Form A, which can be prepared by the crystallization method of the third aspect of the invention as follows: the compound of formula III is heated to 80 ° C in an oven to maintain the temperature 10 In minutes, naturally cool to room temperature.
  • the crystal of the fourth aspect of the invention is a crystal of the monohydrate of the compound of Formula III.
  • crystal form C is the most stable crystal form under room temperature chamber humidity, and has low wettability and good physical and chemical stability, especially in comparison with crystal form A and crystal form E. Sex.
  • Form C is the most preferred crystal of the invention.
  • Form C can be prepared by the crystallization method of the fifth aspect of the present invention: the compound of the formula III is dissolved in water, volatilized in a hood for 3 days, then transferred to a vacuum drying oven, and exposed to vacuum for 1 day.
  • the crystal of the sixth aspect of the invention is also referred to herein as Form E, which can be prepared by the crystallization method of the seventh aspect of the invention as follows: a compound of formula III is added to methanol and acetone, wherein the volume ratio of methanol:acetone The ratio was 1:9, the suspension was stirred for 3 days, centrifuged at 10,000 rpm for 3 minutes, and the precipitate was vacuum dried for 1 hour.
  • the solid pharmaceutical preparation of the eighth aspect of the invention comprises Form A, Form C and/or Form E, preferably Form C.
  • Pharmaceutically acceptable excipients as used herein refers to non-toxic fillers, stabilizers, disintegrants, solubilizers or other formulation excipients which are generally solid.
  • the pharmaceutical composition can be formulated into various dosage forms according to the purpose of treatment, such as injection or oral administration, preferably in the form of a unit dosage form such as a powder injection, a tablet or a capsule, etc. More preferably, the pharmaceutical composition is a powder for injection.
  • the solid pharmaceutical preparations can be used to treat or prevent tumor and/or viral infections, for example, for treating or preventing liver cancer, and/or for treating or preventing hepatitis B virus infection.
  • the use of the ninth aspect of the invention may also be converted to a method of treating or preventing a tumor and/or viral infection comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of Form A, Form C and/or Form E Or converted to Form A, Form C and/or Form E for the treatment or prevention of tumor and/or viral infections.
  • the application of the ninth aspect of the invention is the application of Form C.
  • the tumor is liver cancer; and/or the virus is hepatitis B virus.
  • the drug is a solid drug.
  • the method for synthesizing the trathacitabine of the invention has high purity, especially can be scaled up, and is suitable for industrial production; the crystal of the invention (especially the crystal form C) is stable, has low hygroscopicity, and is particularly suitable for storage as a solid drug. And transportation.
  • Figures 1-3 show the characterization of Form A, where Figure 1 shows the XRPD pattern of Form A; Figure 2 shows the TGA/DSC overlay of Form A; Figure 3 shows the 1H NMR spectrum of Form A Figure.
  • Figure 4-6 shows a characterization map of Form C, where Figure 4 shows the XRPD pattern of Form C (the overlap pattern repeated twice in parallel); Figure 5 shows the TGA/DSC overlay of Form C; 6 shows the XRPD overlap spectrum of Form A before and after heating and Form A.
  • Figures 7-9 show the characterization of Form E, where Figure 7 shows the XRPD pattern of Form E (the overlap pattern repeated twice in parallel); Figure 8 shows Form E heating, before and after placement and Form A X, XRPD overlap spectrum; Figure 9 shows the pattern E heating, DSC overlap map before and after placement.
  • the temperature in the autoclave was continuously maintained at 0 ⁇ 3 ° C, and 3.64 g of hexamethyldisilazane and 1.15 g of N 4 -acetylcytosine were slowly added dropwise.
  • the organic phase was washed once with a saturated brine (11.3 g), and the organic phase was separated and dried over anhydrous sodium sulfate overnight to remove water.
  • the sodium sulfate solid was filtered off and the filtrate was transferred to a rotary evaporator at a temperature not exceeding 45 ° C until the end of distillation.
  • the residue obtained by rotary evaporation was transferred to a reaction vessel, and 11.2 g of acetone and 18.5 g of isopropyl acetate were added, and the mixture was heated to reflux (68 ⁇ 3 ° C), and stirred to form a slurry for 1 hour. Slowly cool down within 2.5 ⁇ 0.5 hours until the temperature in the kettle is 22 ⁇ 3 °C.
  • the filter cake was quickly filtered, and the filter cake was placed in a vacuum oven at about 40 ° C under vacuum overnight to obtain a white solid (crude of formula II) to be used.
  • the diatomaceous earth filter cake obtained by the above filtration was transferred to a reaction vessel, and the temperature was raised to 27 ⁇ 3 ° C, and 18.0 g of dichloromethane was added thereto, and the mixture was stirred and stirred for 2 hours.
  • the slurry was filtered and the filtrate was transferred to a rotary evaporator at a temperature not exceeding 45 ° C until the end of the distillation.
  • the amount was 13.3 g of isopropyl acetate + 7.9 g of acetone), and the mixture was heated to reflux (68 ⁇ 3 ° C), and stirred to form a slurry for 1 hour.
  • the temperature was slowly lowered to a temperature of 22 ⁇ 3 ° C in the kettle.
  • the filter cake was quickly filtered and the filter cake was washed once with cold acetone 1.5 g.
  • the filter cake was placed in a vacuum oven at about 40 ° C under vacuum overnight to give a fine formula II.
  • the mixture was slowly cooled (2.5 ⁇ 0.5 hours) to room temperature, and stirred at room temperature for 12 hours. Continue to cool down to 2.5 ⁇ 2.5 ° C, and stir at this temperature for 4.5 ⁇ 0.5 hours. After filtration, the filter cake was washed once with 1.0 g of cold ethanol, filtered thoroughly, and the filtrate was discarded. The filter cake was transferred to a vacuum oven and dried to constant weight at 38 ⁇ 2 ° C to obtain a fine formula III, and the purity was determined by HPLC.
  • the above method can be scaled up stably, for example, it can be directly placed about 60-180 times or more, that is, the formula I is fed with 61.7 g to 185.97 g (other reactants are equally increased), and the final product (formula III) is purified by HPLC. It is 99.3% to 99.8%, and the yield is 65-85%, which fully satisfies the industrialization needs of tresalabine.
  • the inventors used seven methods and set up 103 polymorphic screening experiments, and selected seven crystal forms, namely crystal forms A, B, C, E, F, J and K, of which crystal form B, F and J are unstable at room temperature, while Form K is a crystalline form of acetic acid solvate or acetate of trazacitabine, and Form C is a crystalline form of trihydrate of trazacitabine, Form A And E is the crystal form of trozaplatin itself (anhydrous).
  • FIG. 1 shows the XRPD pattern of Form A
  • Figure 2 shows the TGA/DSC overlay of Form A, where the sample is heated to 150 ° C with a weight loss of 1.9% and a melting point of 198.9 ° C. (Starting temperature), the crystal form A was shown to be crystal-free
  • FIG. 3 shows the 1H NMR spectrum of the crystal form A.
  • the XRPD pattern (the overlapping pattern repeated twice in parallel) indicates that the positions of the peaks are stable;
  • Figure 8 shows the XRPD pattern (overlapped spectrum) of the crystal form E before and after the addition and the crystal forms A and C, wherein the crystal form E sample After 3 days of standing, the diffraction peak of Form C appeared in the XRPD pattern, indicating that the Form E had a tendency to change to Form C after being placed in the air, and the diffraction peak of Form C disappeared on the XRPD pattern after heating to 100 °C.
  • FIG. 9 shows the DSC pattern (overlapped map) before and after the heating of Form E, where the Form E sample was placed for 3 days, on the DSC chart.
  • Three endothermic peaks appear, indicating a mixture of Forms C and E, and the first endothermic peak on the DSC pattern after heating to 100 °C (the first endothermic peak (68.3 ° C, starting temperature) is crystalline
  • the dehydration peak of C disappears.
  • the second endothermic peak disappears on the DSC chart, that is, the second endothermic peak (146.0 ° C, starting temperature) is crystal Transfected into E starts crystalline Form A peaks.
  • Form A sample is partially converted to Form C after being left for one month, and thus the in-depth study of these crystal forms has begun.
  • Form A began to absorb water at 70% RH and 8.4% by 90% RH.
  • XRPD showed that it began to transform into crystal after water absorption.
  • Form C begins to absorb water at 80% RH, and absorbs 8.5% at 90% RH.
  • XRPD shows that it begins to change to Form C after water absorption; Form C at 25 ° C / 80% RH
  • the wettability was 0.14%, and it was not easy to remove under low humidity, indicating that the crystal water in the crystal form C was firmly bound, and the XRPD showed that the crystal form C remained unchanged before and after the DVS test. Therefore, the hydrate crystal form C is the most stable crystal form under room temperature chamber humidity, so the crystal form C is selected for further stability studies.
  • Form C was placed at 80 ° C (closed) for 24 hours and 40 ° C / 75% RH, 25 ° C / 60% RH open for 1 week for physicochemical stability evaluation, by XRPD, TGA, DSC and The chemical and physical stability of the samples were tested by HPLC.
  • the test data are summarized in Table 1, indicating that Form C has good physical stability under conditions of 40 ° C / 75% RH, 25 ° C / 60% RH (conventional drug storage and transportation conditions), and chemical purity analysis results show that travertabine is in The purity of these three conditions did not change, indicating that Form C has good chemical stability.

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Abstract

本发明提供了曲沙他滨的合成方法和结晶方法等。另外,本发明还提供了曲沙他滨的晶型及其应用等。

Description

曲沙他滨的合成及其晶型 技术领域
本发明属于药物化学领域,具体而言,本发明涉及曲沙他滨的合成方法及其晶型等。
背景技术
曲沙他滨(4-氨基-1-[(2S,4S)-2-(羟甲基)-1,3-二氧杂环戊-4-基]嘧啶-2-酮,Troxacitabine,TroxatylTM)是由美国耶鲁大学研发的抗肿瘤胞苷类似物。在美国的多年I期/II期临床研究中,采用各种剂量方案,进行了曲沙他滨单独给药或与其它化疗剂混合给药,治疗了逾825例患有多种实体肿瘤或血液恶性肿瘤的病人。尤其是,曲沙他滨同时具有抑制乙肝病毒和抗肝癌细胞生长的特性。
中国专利申请第201310275643.2号公开了一种曲沙他滨的合成方法,该方法以二羟基乙酸L-薄荷醇酯为原料,与羟基乙醛发生缩合反应,然后其羟基经卤代后得到卤代物,卤代物与胞嘧啶耦合后得到耦合物,耦合物再经还原得到曲沙他滨。然而,本发明人发现,该方法需要经过缩合、卤代、耦合和还原等四步需要在不同反应体系中进行的反应,步骤长且繁琐,尤其是中间产物多,需要多次分离而更换反应容器,并且不适合放大,所以十分不适合产业化生产。
经本发明人长期研究和实验,设计出了通过两步反应即可获得曲沙他滨的合成方法,步骤简单,尤其是适合放大,非常适合用于产业化生产;更为令人意想不到的是,该方法合成(尤其是经过精纯化)的产物给本发明人以可能存在多种晶型的提示,为此,本发明人深入研究,获得了曲沙他滨的多种晶型,尤其是室温室湿下稳定的晶型,更加便于推广应用。
发明简述
本发明提供了曲沙他滨的合成方法、曲沙他滨的晶体、晶体的结晶方法以及晶体的应用等。
具体而言,在第一方面,本发明提供了式III化合物的合成方法,其合成反应式如下所示:
Figure PCTCN2016079606-appb-000001
在第二方面,本发明提供了式III化合物的晶体(晶型A),其具有基本上如图1或7所示的X射线粉末衍射图谱
Figure PCTCN2016079606-appb-000002
在第三方面,本发明提供了晶型A的结晶方法,其包括:将式III化合物用烘箱加热至80℃,保持该温度10分钟,自然冷却至室温。
在第四方面,本发明提供了式III化合物的一水合物的晶体(晶型C),其具有基本上如图4所示的X射线粉末衍射图谱
Figure PCTCN2016079606-appb-000003
在第五方面,本发明提供了晶型C的结晶方法,其包括:将式III化合物加入水溶解,在通风橱中敞口挥发3天,然后移入真空干燥箱中,敞口真空挥发1 天。
在第六方面,本发明提供了式III化合物的晶体(晶型E),其具有基本上如图7所示的X射线粉末衍射图谱
Figure PCTCN2016079606-appb-000004
在第七方面,本发明提供了晶型E的结晶方法,其包括:将式III化合物加入甲醇和丙酮,其中甲醇:丙酮的体积比为1:9,将混悬液搅拌3天,以10000rpm离心分离3分钟,沉淀真空干燥1小时。
在第八方面,本发明提供了固体药物制剂,其包括晶型A、晶型C和/或晶型E,以及药学上可接受的辅料。
在第九方面,本发明提供了晶型A、晶型C和/或晶型E在制备抗肿瘤和/或抗病毒的药物中的应用。
发明详述
本发明第一方面的合成方法是新的曲沙他滨的合成方法。该方法包括两步化学反应和相应的纯化方法,适合产业化生产。
优选的本发明第一方面的合成方法包括:
(1)合成:混合式I化合物和二氯甲烷,在惰性气体(优选是氮气)保护下,在0±3℃,滴入三甲基碘硅烷,然后搅拌反应2.5±0.5小时,再加入六甲基二硅胺烷和N4-乙酰胞嘧啶,然后搅拌反应3.5±0.5小时;
纯化:将上述反应体系升温并保持在22±3℃,滴入硫代硫酸钠,然后加入硅藻土,搅拌,过滤,其中,滤饼洗涤后,在27±3℃,加入二氯甲烷,搅拌,过滤,然后去除溶剂,得到的滤饼处理的固体;滤液和滤饼洗涤的洗涤液合并,分出有机相,洗涤后干燥,过滤,对滤液去除溶剂,将得到的残留物混合丙酮和乙酸异丙酯,加热回流,搅拌,然后降温至22±3℃,过滤,干燥,得到滤液处理的固体;将上述滤饼处理的固体和滤液处理的固体合并,加入乙酸异丙酯和丙 酮,加热至回流,搅拌,然后降温至22±3℃,过滤,洗涤,干燥,得到式II化合物;
(2)合成:混合步骤(1)得到的式II化合物和甲醇,搅拌,再滴入甲醇钠的甲醇溶液,在22.5±2.5℃反应1±0.5小时;
纯化:在0±3℃,将上述反应体系pH调至6.5±0.5,然后上样于硅胶层析柱,洗脱并收集含式III化合物的馏分,蒸干后加入无水乙醇,搅拌,加热回流,降温至室温下搅拌12±2小时,然后降温至2.5±2.5℃搅拌4.5±0.5小时,过滤,滤饼洗涤后抽滤,干燥,得到式III化合物。
更优选在本发明第一方面的合成方法中,在步骤(1)的合成步骤中,式I化合物:二氯甲烷:三甲基碘硅烷:六甲基二硅胺烷:N4-乙酰胞嘧啶的重量比为1:18.0:1.5:3.64:1.15。
也更优选在本发明第一方面的合成方法中,在步骤(2)的合成步骤中,式II化合物:甲醇的重量比为1:0.045。
也更优选在本发明第一方面的合成方法中,在步骤(2)的纯化步骤中,硅胶层析柱,洗脱剂为二氯甲烷和甲醇。进一步优选其中,二氯甲烷:甲醇的体积比为4:1。
进一步优选本发明第一方面的合成方法包括结晶的步骤,即在步骤(2)的纯化步骤完成后,进一步进行结晶的步骤。优选所述结晶的步骤选自下列(a)、(b)和(c)之一:
(a)将式III化合物用烘箱加热至80℃,保持该温度10分钟,自然冷却至室温;
(b)将式III化合物加入水溶解,在通风橱中敞口挥发3天,然后移入真空干燥箱中,敞口真空挥发1天;
(c)将式III化合物加入甲醇和丙酮,其中甲醇:丙酮的体积比为1:9,将混悬液搅拌3天,以10000rpm离心分离3分钟,沉淀真空干燥1小时。
这些结晶步骤分别制备获得晶型A、晶型C和晶型E。
本发明第二方面的晶体在本文中也被称为晶型A,其可以通过如下的本发明的第三方面的结晶方法制备:将式III化合物用烘箱加热至80℃,保持该温度10 分钟,自然冷却至室温。
本发明第四方面的晶体在本文中也被称为晶型C,是式III化合物的一水合物的晶体。与本发明人发现的七种晶体相比,尤其与晶型A和晶型E相比,晶型C是室温室湿下最稳定的晶型,引湿性低,而且具有良好的物理和化学稳定性。因此晶型C是本发明最优选的晶体。晶型C可以通过如下的本发明的第五方面的结晶方法制备:将式III化合物加入水溶解,在通风橱中敞口挥发3天,然后移入真空干燥箱中,敞口真空挥发1天。
本发明第六方面的晶体在本文中也被称为晶型E,其可以通过如下的本发明的第七方面的结晶方法制备:将式III化合物加入甲醇和丙酮,其中甲醇:丙酮的体积比为1:9,将混悬液搅拌3天,以10000rpm离心分离3分钟,沉淀真空干燥1小时。
本发明第八方面的固体药物制剂包括晶型A、晶型C和/或晶型E,优选包括晶型C。本文中使用的药学上可接受的辅料指无毒的填充剂、稳定剂、崩解剂、增溶剂或其他制剂辅料,它们通常是固体的。本领域的技术人员可以根据治疗目的、给药途径(如注射或口服)的需要将药物组合物制成各种剂型,优选该组合物为单位剂量形式,如粉针剂、片剂或胶囊等,更优选该药物组合物为注射用粉针剂。
该固体药物制剂可以用于治疗或预防肿瘤和/或病毒感染,例如,用于治疗或预防肝癌,和/或,用于治疗或预防乙肝病毒感染。
本发明第九方面的应用也可以转换成治疗或预防肿瘤和/或病毒感染的方法,其包括向有需要的个体施用治疗或预防有效量的晶型A、晶型C和/或晶型E;或者转换成晶型A、晶型C和/或晶型E,其用于治疗或预防肿瘤和/或病毒感染。
优选本发明第九方面的应用是晶型C的应用。
也优选在本发明第九方面的应用中,肿瘤是肝癌;和/或,病毒是乙肝病毒。
进一步地,优选在本发明第九方面的应用中,药物是固体药物。
本发明的曲沙他滨的合成方法产物纯度高,尤其可以等比例放大,适合产业化生产;本发明的晶体(尤其是晶型C)稳定,引湿性低,特别适用于作为固体药物而储存和运输。
为了便于理解,本发明引用了公开文献,这些文献是为了更清楚地描述本发明,其全文内容均纳入本文进行参考。
以下将通过具体的实施例和附图对本发明进行详细地描述。需要特别指出的是,这些描述仅仅是示例性的描述,并不构成对本发明范围的限制。依据本说明书的论述,本发明的许多变化、改变对所属领域技术人员来说都是显而易见了。
附图说明
图1-3显示了晶型A的表征图谱,其中图1显示了晶型A的XRPD图谱;图2显示了晶型A的TGA/DSC重叠图谱;图3显示了晶型A的1H NMR谱图。
图4-6显示了晶型C的表征图谱,其中图4显示了晶型C的XRPD图谱(平行试验重复两次的重叠图谱);图5显示了晶型C的TGA/DSC重叠图谱;图6显示了晶型C加热前后和晶型A的XRPD重叠谱图。
图7-9显示了晶型E的表征图谱,其中图7显示了晶型E的XRPD图谱(平行试验重复两次的重叠图谱);图8显示了晶型E加热、放置前后及晶型A、C的XRPD重叠谱图;图9显示了晶型E加热、放置前后的DSC重叠图谱。
具体实施方式
下面将通过实施例的方式进行说明。
实施例1 曲沙他滨的合成
合成路线如下反应式所示:
Figure PCTCN2016079606-appb-000005
第一步:式II的制备
反应釜中依次加入二氯甲烷18.0g、式I 1g搅拌均匀;氮气保护下,降温至釜内温0±3℃后,缓慢滴入三甲基碘硅烷1.5g;保持釜内温0±3℃,氮气保护下搅拌2.5±0.5小时,直至反应完全(取样TLC检测:展开剂:石油醚:乙酸乙酯=4:1(v/v),Rf=0.5处点消失)。随后继续保持釜内温度为0±3℃依次缓慢滴入六甲基二硅胺烷3.64g和N4-乙酰胞嘧啶1.15g。加料完成后控制釜内温度0±3℃,氮气保护下搅拌反应3.5±0.5小时,直至反应完全(取样TLC检测:展开剂:石油醚:乙酸乙酯=4:1(v/v),Rf=0.2处点消失)。
然后升温,保持釜内温度在22±3℃下,缓慢滴入10%%(w/w)硫代硫酸钠水溶液,滴加5g硫代硫酸钠水溶液后,加入硅藻土0.5g,搅拌1小时。过滤,滤饼用二氯甲烷打浆洗涤3次,滤饼收集待用。滤液和洗涤液合并转入釜中,分出水相和有机相,有机相使用饱和食盐水11.3g洗涤一次,分出有机相,用无水硫酸钠干燥过夜,用以去除其中的水分。滤除硫酸钠固体,滤液转入旋转蒸发器,旋蒸温度不超过45℃,直至蒸馏结束。将旋蒸得到的残留物转移至反应釜中,加入丙酮11.2g,乙酸异丙酯18.5g,加热至回流(68±3℃),搅拌成浆状,保持1小时。在2.5±0.5小时内,缓慢降温,直至釜内温度为22±3℃。快速过滤,滤饼置于真空干燥箱中约40℃真空干燥过夜,得到的白色固体(式II粗品)待用。
上步过滤得到的硅藻土滤饼转移至反应釜中,升温至27±3℃,加入二氯甲烷18.0g,搅拌成浆状,搅拌2小时。过滤浆液,滤液转入旋转蒸发器,旋蒸温度不超过45℃,直至蒸馏结束。将旋蒸得到的固体(式II粗品)和上步待用的白色固体合并转移至反应釜中,加入乙酸异丙酯:丙酮=3:2(v/v)混合溶剂(以1g式II粗品计,加入量为13.3g乙酸异丙酯+7.9g丙酮),加热至回流(68±3℃),搅拌成浆状,保持1小时。在2.5±0.5小时内,缓慢降温,至釜内温度为22±3℃。快速过滤,滤饼用冷丙酮1.5g洗涤一次。滤饼置于真空干燥箱中约40℃真空干燥过夜,得到式II精品。
第二步:式III的制备及精制
取式II精品1g加入到四口瓶中,加入甲醇5.0g,搅拌使固体分散均匀。称取甲醇钠0.045g,加入到0.135g甲醇中,搅拌使甲醇钠溶解。向四口瓶中滴入 上述甲醇钠的甲醇溶液。22.5±2.5℃下保温反应1小时,直至反应完全(取样TLC检测:展开剂:二氯甲烷:甲醇=4:1(v/v),Rf=0.8处点消失)。
反应完全后,在冰浴下,用冰乙酸调节体系pH至6.5±0.5。然后向其中加入200-300目硅胶(可购自青岛海洋化工厂分厂)10g制砂,填充层析柱,进行柱层析,其中洗脱剂为二氯甲烷:甲醇=4:1(v/v),收集含曲沙他滨的馏分,旋蒸至干。将旋蒸后的固体转移到三口瓶中,加入无水乙醇3.0g,搅拌分散均匀(悬混),加热至78±2℃回流0.5小时。回流完成后,缓慢(2.5±0.5小时)降温至室温,在室温下搅拌12小时。继续降温至2.5±2.5℃,在此温度下保温搅拌4.5±0.5小时。过滤,滤饼用1.0g冷乙醇洗涤一次,彻底抽滤,滤液弃去。滤饼转移至真空烘箱中,38±2℃下干燥至恒重,得式III精品,用HPLC检测纯度。
以上方法可以等比例稳定放大,例如可以直接放大约60~180倍以上,即式I投料61.7g~185.97g(其他反应物均等比例增加),放大后最终产物(式III精品)的HPLC检测纯度为99.3%~99.8%,收率为65~85%,完全满足了曲沙他滨药用的产业化需要。
实施例2 曲沙他滨的晶型
本发明人使用了7种方法,设置了103个多晶型筛选实验,从中筛选出7种晶型,分别为晶型A、B、C、E、F、J和K,其中晶型B、F和J在常温下不稳定,而晶型K为曲沙他滨的醋酸溶剂合物或醋酸盐的晶型,晶型C为曲沙他滨的一水合物的晶型,晶型A和E为曲沙他滨本身(无水物)的晶型。
一,晶型A
取根据实施例1获得的最终产物300.5mg,置于5mL小瓶中,用烘箱加热至80℃,保持该温度10分钟,自然冷却至室温。所得的晶型被命名为晶型A,用X射线粉末衍射(XRPD)、热重分析(TGA)和差示扫描量热(DSC)以及液态核磁氢谱(1H liquid NMR)等方法表征,结果如图1-3所示,其中图1显示了晶型A的XRPD图谱;图2显示了晶型A的TGA/DSC重叠图谱,其中样品加热至150℃失重为1.9%,且熔点为198.9℃(起始温度),显示晶型A为无水晶型;图3显示了晶型A的1H NMR谱图。
二,晶型C
取根据实施例1获得的最终产物201.3mg,置于5mL小瓶中,加入0.8mL水溶解,在通风橱中敞口挥发3天,然后移入真空干燥箱中,敞口真空(<-100KPa)挥发1天。所得的晶型被命名为晶型C,用X射线粉末衍射(XRPD)、热重分析(TGA)和差示扫描量热(DSC)等方法表征,结果如图4-6所示,其中图4显示了晶型C的XRPD图谱(平行试验重复两次的重叠图谱),表明各峰位置稳定;图5显示了晶型C的TGA/DSC重叠图谱,其中样品加热至100℃时失重为7.3%(一水合物理论失重为7.8%),并在74.1℃(峰温)、92.5℃(峰温)以及198.1℃(起始温度)出现3个吸热峰;图6显示了晶型C加热前后和晶型A的XRPD图谱(重叠谱图),当加热至100℃,晶型C开始转变为晶型A,结合7.3%的TGA失重,表明晶型C为一水合物。
三,晶型E
取根据实施例1获得的最终产物199.8mg,置于5mL小瓶中,加入4.0mL甲醇:丙酮=1:9(v/v),将混悬液搅拌3天,以10000rpm离心分离3分钟,沉淀真空干燥1小时。所得的晶型被命名为晶型E,用X射线粉末衍射(XRPD)和差示扫描量热(DSC)等方法表征,结果如图7-9所示,其中图7显示了晶型E的XRPD图谱(平行试验重复两次的重叠图谱),表明各峰位置稳定;图8显示了晶型E加热、放置前后和晶型A、C的XRPD图谱(重叠谱图),其中晶型E样品放置3天后,XRPD图中出现晶型C的衍射峰,说明晶型E在空气中放置后有转变成晶型C的趋势,而加热至100℃后XRPD图上晶型C的衍射峰峰消失,加热至160℃后XRPD结果显示晶型E开始转变为晶型A;图9显示了晶型E加热、放置前后的DSC图谱(重叠图谱),其中晶型E样品放置3天后,DSC图上出现3个吸热峰,表明出现晶型C和E的混合物,而加热至100℃后DSC图上第一个吸热峰(第一个吸热峰(68.3℃,起始温度)为晶型C的脱水峰)消失,加热至160℃后DSC图上第二个吸热峰消失,即该第二个吸热峰(146.0℃,起始温度)为晶型E开始转变为晶型A的转晶峰。
实施例3 曲沙他滨的晶型A、C、E的性质研究
本发明人发现,晶型A样品在放置1个月后会部分转为晶型C,因此开始更深入地研究这些晶型。
一,引湿性研究
晶型A、C和E的引湿性通过25℃下的DVS测试进行评估,晶型A在70%RH条件下开始吸水,到90%RH吸水8.4%,XRPD显示其在吸水后开始转变为晶型C;晶型E在80%RH条件下开始吸水,到90%RH时吸水8.5%,XRPD显示其在吸水后开始转变为晶型C;晶型C在25℃/80%RH下的引湿性为0.14%,而且在低湿度下不易脱去,表明晶型C中的结晶水绑定牢固,XRPD显示晶型C在DVS测试前后晶型不变。所以,水合物晶型C是室温室湿下最稳定的晶型,因此选择晶型C进一步进行稳定性研究。
二,稳定性研究
将晶型C在80℃条件下(闭口)放置24小时以及40℃/75%RH,25℃/60%RH条件下敞口放置1周进行物理化学稳定性评估,通过XRPD,TGA,DSC和HPLC测试样品的化学和物理稳定性。测试数据总结在表1中,表明晶型C在40℃/75%RH,25℃/60%RH条件(常规药物储运条件)下物理稳定性良好,化学纯度分析结果显示曲沙他滨在这3种条件下纯度均未改变,表明晶型C具有良好的化学稳定性。
表1 晶型C稳定性试验数据
Figure PCTCN2016079606-appb-000006
*:起始温度。

Claims (10)

  1. 式III化合物的合成方法,其合成反应式如下所示:
    Figure PCTCN2016079606-appb-100001
  2. 权利要求1所述的方法,其包括:
    (1)合成:混合式I化合物和二氯甲烷,在惰性气体(优选是氮气)保护下,在0±3℃,滴入三甲基碘硅烷,然后搅拌反应2.5±0.5小时,再加入六甲基二硅胺烷和N4-乙酰胞嘧啶,然后搅拌反应3.5±0.5小时;
    纯化:将上述反应体系升温并保持在22±3℃,滴入硫代硫酸钠,然后加入硅藻土,搅拌,过滤,其中,滤饼洗涤后,在27±3℃,加入二氯甲烷,搅拌,过滤,然后去除溶剂,得到的滤饼处理的固体;滤液和滤饼洗涤的洗涤液合并,分出有机相,洗涤后干燥,过滤,对滤液去除溶剂,将得到的残留物混合丙酮和乙酸异丙酯,加热回流,搅拌,然后降温至22±3℃,过滤,干燥,得到滤液处理的固体;将上述滤饼处理的固体和滤液处理的固体合并,加入乙酸异丙酯和丙酮,加热至回流,搅拌,然后降温至22±3℃,过滤,洗涤,干燥,得到式II化合物;
    (2)合成:混合步骤(1)得到的式II化合物和甲醇,搅拌,再滴入甲醇钠的甲醇溶液,在22.5±2.5℃反应1±0.5小时;
    纯化:在0±3℃,将上述反应体系pH调至6.5±0.5,然后上样于硅胶层析柱,洗脱并收集含式III化合物的馏分,蒸干后加入无水乙醇,搅拌,加热回流,降温至室温下搅拌12±2小时,然后降温至2.5±2.5℃搅拌4.5±0.5小时,过滤,滤 饼洗涤后抽滤,干燥,得到式III化合物。
  3. 权利要求2所述的方法,其中,在步骤(1)的合成步骤中,式I化合物:二氯甲烷:三甲基碘硅烷:六甲基二硅胺烷:N4-乙酰胞嘧啶的重量比为1:18.0:1.5:3.64:1.15;和/或,在步骤(2)的合成步骤中,式II化合物:甲醇的重量比为1:0.045。
  4. 权利要求2所述的方法,其中,在步骤(2)的纯化步骤中,硅胶层析柱,洗脱剂为二氯甲烷和甲醇,优选二氯甲烷:甲醇的体积比为4:1。
  5. 权利要求2所述的方法,其还进一步包括结晶的步骤,优选所述结晶的步骤选自下列(a)、(b)和(c)之一:
    (a)将式III化合物用烘箱加热至80℃,保持该温度10分钟,自然冷却至室温;
    (b)将式III化合物加入水溶解,在通风橱中敞口挥发3天,然后移入真空干燥箱中,敞口真空挥发1天;
    (c)将式III化合物加入甲醇和丙酮,其中甲醇:丙酮的体积比为1:9,将混悬液搅拌3天,以10000rpm离心分离3分钟,沉淀真空干燥1小时。
  6. 式III化合物晶体,其具有基本上如图1或7所示的X射线粉末衍射图谱
    Figure PCTCN2016079606-appb-100002
  7. 式III化合物的一水合物的晶体,其具有基本上如图4所示的X射线粉末衍射图谱
    Figure PCTCN2016079606-appb-100003
  8. 权利要求6或7所述的晶体,其是通过权利要求5所述的方法制备的。
  9. 固体药物制剂,其包括权利要求6~8之任一所述的晶体和药学上可接受的辅 料。
  10. 权利要求6~8之任一所述的晶体在制备抗肿瘤(如,肝癌)和/或抗病毒(如,乙肝病毒)的药物中的应用。
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